A dynamic model for the allosteric mechanism of GroEL

GroEL-assisted protein folding is regulated by a cycle of large coordinated domain movements in the 14-subunit double-ring assembly. The transition pa th between the closed (unliganded) and the open (liganded) states, calculat ed with a targeted molecular dynamics simulation, shows the highly complex subunit displacements required for the allosteric transition. The early dow nward motion of the small intermediate domain induced by nucleotide binding emerges as the trigger for the larger movements of the apical and equatori al domains. The combined twisting and upward displacement of the apical dom ain determined for a single subunit is accommodated easily in the heptamer ring only if its opening is concerted. This is a major source of cooperativ e ligand binding within a ring. It suggests also that GroEL has evolved so that the motion required for heptamer cooperativity is encoded in the indiv idual subunits. A calculated model for a di-cis 14-subunit assembly is foun d to be destabilized by strong steric repulsion between the equatorial doma ins of the two rings, the source of negative cooperativity. The simulation results, which indicate that transient interactions along the transition pa th are essential for GroEL function, provide a detailed structural descript ion of the motions that are involved in the GroEL allosteric cycle. (C) 200 0 Academic Press.